Although intracellular Ca++ is required for smooth muscle contraction, the sensitivity of contraction to Ca++ is variable. Several hormones/agonists, for example, increase the force of contraction at a given submaximal intracellular [Ca++], thereby resulting in Ca++ sensitization (
Fig.
14.8 ). Ca++ sensitization is depicted as a leftward shift in the Ca++ dependence of smooth muscle contraction (see
Fig. 14.8B ) and can occur in response to a decrease in the activity of MP activity at a given intracellular [Ca++]. Likewise an increase in MP activity at a given intracellular [Ca++] promotes a rightward shift in the Ca++ dependence of smooth muscle contraction, resulting in Ca++ desensitization (see
Fig. 14.8B ). Reciprocal changes in the activities of MP and MLCK can occur, as shown in
Fig. 14.8A , where stimulation of the ROK signaling cascade by an agonist can simultaneously inhibit MP and stimulate MLCK at a given intracellular [Ca++], thereby increasing the Ca++ sensitivity of contraction (i.e., Ca++ sensitization).
Fig.
14.8A ).RhoAactivatesRhokinase(ROK),whichinturninhibitsMPbybothdirectandindirectmechanisms.DirectinhibitionofMPbyactivatedROKinvolvesROKphosphorylationofthemyosin-bindingsubunit(MBS)ofMP.IndirectinhibitionofMPbyactivatedROKinvolvesphosphorylationofCPI-17, anendogenous17-kDaprotein,whichtheninhibitsMP.Hormones/agonistssuchascatecholamines(actingonα1-adrenergicreceptors),vasopressin,endothelin,angiotensin,andmuscarinicagonistsincreasethesensitivityofsmoothmusclecontractiontoCa++ throughactivationofRhoA/ROKsignaling.ROKcanalsobeactivatedbyarachidonicacidandinhibitedbyY-27632,ahighlyspecificinhibitor(see
Fig.14.8A ).Thoughnotshownin
Fig.14.8 ,inactiveRhoAistypicallylocatedinthecytosol,boundtoGDPandaninhibitoryprotein(Rho-GDP dissociation inhibitor [GDI]). BindingofagonisttovariousG-coupledreceptorscanactivateRhoAbystimulatingguanine nucleotide exchange factor (GEF) toyieldRhoA-GTP,whichlocalizestothesarcolemmaandactivatesROK.Conversely,stimulationofMPactivityreducestheCa++ sensitivityofcontractionofsmoothmuscle,therebypromotingrelaxation(andhencevasodilation).